Burkitt Lymphoma in the Mouse

Abstract

Chromosomal translocations juxtaposing the MYC protooncogene with regulatory sequences of immunoglobulin (Ig) H chain or kappa (Igκ) or lambda (Igλ) L chain genes and effecting deregulated expression of MYC are the hallmarks of human Burkitt lymphoma (BL). Here we report that lymphomas with striking similarities to BL develop in mice bearing a mutated human MYC gene controlled by a reconstructed Igλ locus encompassing all the elements required for establishment of locus control in vitro. Diffusely infiltrating lymphomas with a typical starry sky appearance occurred in multiple founders and an established line, indicating independence from positional effects. Monoclonal IgM+CD5−CD23− tumors developed from an initially polyclonal population of B cells. These results demonstrate that the phenotype of B lineage lymphomas induced by MYC dysregulation is highly dependent on cooperativity among the regulatory elements that govern expression of the protooncogene and provide a new system for studying the pathogenesis of BL.

Requirements for control of B‐cell lymphoma by NK cells

“…Activation status and effector functions of NK cells in mice developing spontaneous lymphoma l-myc transgenic mice express the myc oncogene under the control of Ig-l chain regulatory sequences and spontaneously develop tumors of the B-cell lineage that share multiple features of human Burkitt lymphoma [29]. Animals with lymphadenopathy were sacrificed and NK cells from spleens and lymph nodes were phenotypically analyzed.…”

“…C57BL/6 and BALB/c WT mice were purchased from Bommice (Ry, Denmark). l-myc mice [29] are of C57BL/6 origin and were bred in our own facility. All animal experiments were in accordance with relevant regulations and had been approved by the Regierung von Oberbayern.…”

“…We previously showed that missing self can induce strong and protective NK-cell responses in a tumor transplantation model [6], but this may not reflect the situation in endogenous tumors. Therefore, we used a c-myc transgenic model of spontaneously arising lymphoma [29] and analyzed lack of inhibiting and presence of NKG2D-mediated activating signals in the light of the two-step NK-cell activation hypothesis. We show that the two-stage activation process that was previously described only in vitro [26] can adequately explain the situation in vivo.…”

c-MYC activates protein kinase A (PKA) by direct transcriptional activation of the PKA catalytic subunit beta (PKA-Cβ) gene

“…Northern blot analysis of these cell lines showed that the expression of PKA-Cb RNA was significantly increased (*10-fold) in CBMyc.Max cells when compared to control transfected cells (CB control) or CBMax cells (Figure 1b, left panel). Furthermore, PKA-Cb RNA levels were decreased in U937 cells induced to terminal monocytic differentiation by phorbol 12-myristate 13-acetate (TPA) treatment, a process that requires down-regulation of c-MYC expression (Larsson et al, 1988) (Figure 1b To verify the relationship between c-MYC deregulation and PKA-Cb gene expression in vivo, we performed Western blot analysis of B cells purified from the spleen of mice expressing a transgenic l-MYC construct driven by B cell specific transcriptional regulatory elements (Kovalchuk et al, 2000). Figure 1d shows that CD19+ cells from two transgenic l-MYC mice, but not those from wild-type littermate controls, overexpress both c-MYC and PKA-Cb.…”

Genomic instability in mouse Burkitt lymphoma is dominated by illegitimate genetic recombinations, not point mutations

“…The l-MYC transgene utilizes the 3' enhancer and other regulatory elements of the human immunoglobulin light-chain l locus to enforce the expression of human MYC in B cells. All l-MYC mice develop lymphomas with striking similarities to human Burkitt lymphoma (BL) (Kovalchuk et al, 2000). The pUR288 transgene harbors a shuttle vector with a lacZ reporter gene to examine mutagenesis in vivo with greater ease than studying endogenous genes (Boerrigter et al, 1995).…”